PROJECT DESCRIPTION Clear-cell carcinomas (CCCs) are highly aggressive malignancies originated from multiple tissues including the kidney and ovary. Each year, nearly 15,000 patients were killed by CCCs in the U.S.; and the world-wide disease incidences continue to rise, highlighting a pressing unmet medical need. Aiming to identify new therapeutic targets in CCCs, the PI recently revealed a unique vulnerability to ferroptosis in various CCC models. Ferroptosis is a non-apoptotic form of cell death driven by membrane accumulation of radical species from unsaturated lipids. Importantly, ferroptosis is also a targetable vulnerability in drug-resistant cancer cells, and the executioner pathway of cancer immunotherapy. Hence, inducing ferroptosis holds great promise as an emerging therapeutic strategy for cancer treatment. However, it remains elusive as to what makes certain cancer cells especially susceptible to ferroptosis, and how durable ferroptotic responses are in human tumors. The PI?s preliminary studies using animal models suggest that the plasticity in cellular lipid composition may underlie ferroptosis sensitivity and evasion in CCCs. This proposal aims to elucidate how lipid plasticity drives ferroptosis-sensitivity and -resistance, and characterize how unsaturated lipids regulate CCC tumor progression and metastasis. The Specific Aims of this proposal are: 1. Determine the mechanisms underlying ferroptosis sensitivity and polyunsaturated lipid enrichment. 2. Determine the mechanisms driving ferroptosis-resistance in clear-cell carcinomas. 3. Elucidate the role of lipid plasticity in clear-cell carcinoma tumor progression and metastasis. Aim 1 and Aim 2 will be performed during the mentored K99 phase. Aim 3 will be performed in the PI?s own lab in the R00 phase. Success of this work will improve our understanding about cancer lipid metabolism, identify potential therapeutic targets and tool compounds for treating clear-cell carcinomas, and present important insights towards understanding the metabolic basis of cancer development and metastasis. Dr. Yilong Zou is currently a postdoc fellow in the Chemical Biology and Therapeutics Science Program at the Broad Institute. His initial achievement identifies a cross-lineage vulnerability to ferroptosis in clear-cell cancers was recently published in Nature Communications. His long-term goal is to establish an interdisciplinary cancer research lab that integrates cancer biology, metabolism and chemical biology. The proposed research will provide new training for Dr. Zou in chemical biology and cancer metabolism. This work will be performed at the Broad Institute, an exciting research environment with cutting-edge facilities. Dr. Zou will be mentored by Dr. Stuart Schreiber, a pioneer in chemical biology and therapeutics science and a dedicated supporter for young trainees. Together, this career development plan will help Dr. Zou establish his independent research lab at a research-oriented academic institute and become a leader in the field of cancer metabolism and therapeutics.